Table 1.
Some examples of cytochrome-mediated drug interactions that increase morbidity, hospitalization and mortality.
| Cytochrome | Interactions | Type and magnitude of effect | Ref. |
|---|---|---|---|
| 1A2 | Theophylline + ciprofloxacin (1A2 inhibitor) | The coadministration of theophylline with ciprofloxacin, compared with other antibiotics, increases the risk of hospitalization due to theophylline toxicity by almost twofold (adjusted OR: 1.86, 95% CI: 1.18–2.93) | [98] |
| 2C8 | Repaglinide + gemfibrozil (2C8 inhibitor) | Gemfibrozil increases repaglinide AUC and Cmax by 812 and 240%, respectively. Patients have a greater risk of hypoglycemia when receiving gemfibrozil | [99] |
| 2C9 | Warfarin + Trimethoprim/ sulfamethoxazole (TMP/SMX) (SMX 2C9 inhibitor) | The use of TMP/SMX increases the risk of hospitalization due to upper gastrointestinal bleeding fourfold in patients on warfarin (OR: 3.84, 95% CI: 2.33–6.33). An increased risk of hospitalization for gastrointestinal bleeding in warfarin users occurs within 6-10 days of using TMP/SMX compared with other agents (OR: 1.68, 95% CI: 1.21–2.33) | [57,58] |
| 2C9 | Phenytoin + TMP/SMX (SMX 2C9 inhibitor) | Twofold higher risk of hospitalization for phenytoin toxicity with use of TMP/SMX in prior 30 days compared with amoxicillin (OR: 2.11, 95% CI: 1.24–3.60) | [59] |
| 2C9 | Glyburide + TMP/SMX (SMX 2C9 inhibitor) | Elderly patients receiving glyburide admitted with hypoglycemia were 6-times more likely to have been treated with TMP/SMX in the previous week (OR: 6.6, 95% CI: 4.5–9.7). The use of TMP/SMX increases the risk of severe hypoglycemia in glyburide users compared with cephalosporins (OR: 2.68, 95% CI: 1.59–4.52) | [60,61] |
| 2D6 | Tamoxifen + paroxetine (2D6 inhibitor) | An increased risk of death is associated with concomitant use of tamoxifen and paroxetine in women older than 65 years being treated for breast cancer | [47] |
| 3A4 | Nifedipine + erythromycin or clarithromycin (3A4 inhibitors) | In elderly patients taking calcium channel blockers, erythromycin coadministration within the previous 7 days is most strongly associated with hospitalization due to hypotension (OR: 5.8; 95% CI: 2.3–15.0), followed by clarithromycin (OR: 3.7, 95% CI: 2.3–6.1) | [62] |
| 3A4 | Oral contraceptives (ethinyl estradiol and norethindrone) + rifampin (3A4 inducer) | Rifampin decreases ethinyl estradiol AUC by 64%. Unplanned pregnancies have been reported when rifampin is given with oral contraceptives | [100,101] |
| 3A4 | HMG-CoA reductase inhibitors (statins) (atorvastatin, simvastatin and lovastatin) + erythromycin or clarithromycin (3A4 inhibitors) | In a geriatric population, coadministration of a statin with erythromycin or clarithromycin, compared to azithromycin, was associated with an increased risk of hospitalization due to rhabdomyolysis (RR: 2.17, 95% CI: 1.04–4.53) or acute kidney injury (RR: 1.78, 95% CI: 1.49–2.14). Patients on erythromycin or clarithromycin also had an increased risk of mortality (RR: 1.56, 95% CI: 1.36–1.80) | [102] |
| 3A4 | Intra-articular triamcinolone + ritonavir (3A4 inhibitor) | Fifteen case reports of iatrogenic Cushing syndrome with suppression of the hypothalamic–pituitary–adrenal axis associated with intra-articular injections of corticosteroids (primarily triamcinolone) have been reported in patients receiving ritonavir | [103] |
AUC: Area under the concentration–time curve; Cmax: Maximum concentration; OR: Odds ratio; RR: Relative risk.